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Bacteriophages and their immunoregulatory effect

Bacteriophages which are classified as viruses, have opened us to a completely unknown world. Those who have heard of phages are familiar to their unique ability of targeting and killing specific bacteria, which is why they are called bacteria killers. Ridding the body of invading bacteria is a problem that is noticed on the outside. Rarely do we think of the effects on our immune system. It is only when we are faced with the physical effects caused by the limits of our immune system, do we recognise the problem.Another fascinating characteristic that has been discussed about bacteriophages, is their immunomodulation capability. There are a few research works available online, which you can find links to, in this article. Some speak of the immunomodulation affect to be present and effective in patients, whilst others speak of quite the opposite. What is important to keep in mind is that although everyone searches for solid facts, perspective plays a big role on what is presented and how it is seen.

Lytic vs lysogenic replication in bacteriophages

Bacteriophages are far from being simple organisms. They are very complex and our science seems to be scratching the surface in understanding their full potential. One of the unique aspects of bacteriophages is that two defining classifications of phages; virulent and temperate. The virulent phages replicate using the lytic cycle which is a normal viral process which involves the virus to penetrate their host, a specific bacterium, and begin to multiple within the host, leading to the killing of the bacterium. The temperate bacteriophages use both the lytic and lysogenic processes. The lysogenic process involves the phage to embed its DNA into the host’s genome. It does not kill the host rapidly by means of rapid replication, but rather lives quietly within the bacterium genome. When the bacterium replicates, the phage’s DNA is also passed on to the newly formed bacteria. Temperate bacteriophages are able to switch from lysogenic to lytic replication. Should the bacteriophage find itself under circumstances of stress or the need to survive, it will switch to the lytic process.

Phages and immunoregulating properties

The research around the topic of immunomodulation and bacteriophages brought opposing views. Most studies seem to incline towards the aspect that bacteriophages do in fact help modulate our immune system, whilst others claim the opposite. An interesting aspect was noticing that those studies which noted that phages did give a positive immunomodulating effect to patients post therapy, used virulent phages, such as the Escherichia virus T4, that use the lytic cycle in replication.

Research sources:

Phages and immunomodulation

Andrzej Górski, Krystyna Dąbrowska, Ryszard Międzybrodzki, Beata Weber-Dąbrowska, Marzanna Łusiak-Szelachowska, Ewa Jończyk-Matysiak, Jan Borysowski. Published in Future Medicine 2017 | DOI: 10.2217/fmb-2017-0049

Phage Therapy: Beyond Antibacterial Action

Andrzej Górski, Ewa Jończyk-Matysiak, Ryszard Międzybrodzki, Beata Weber-Dąbrowska, Marzanna Łusiak-Szelachowska, Natalia Bagińska, Jan Borysowski, Małgorzata B. Łobocka, Alicja Węgrzyn, Grzegorz Węgrzyn. Published in Frontiers in Medicine 2018 | DOI: 10.3389/fmed.2018.00146

Phage therapy in allergic disorders?

Andrzej Górski, Ewa Jończyk-Matysiak, Marzanna Łusiak-Szelachowska, Ryszard Międzybrodzki, Beata Weber-Dąbrowska, Jan Borysowski. Published in ResearchGate 2018 | DOI: 10.1177/1535370218755658

Do bacteriophage guests protect human health?

Giorgia Guglielmi. Published in Science 2017 | Vol. 358, Issue 6366, pp. 982-983 DOI: 10.1126/science.358.6366.982

Another research concluded with the opposite effect. It states that temperate bacteriophages, which to use the lysogenic replication process, such as the Pseudomonas aeruginosa, has the capability of suppressing phagocytosis. This would result in a negative impact on the immune system. A significant decrease in immunity was observed when mice were infected with the bacterium Pseudomonas aeruginosa with a Pf lysogenic filamentous phage. Pf positive strains are very common in chronic and non-healing wounds in comparison to Pf negative ones. In addition, to obtain the inflammatory process, Pf positive bacteria were required 50 times less than negative Pf bacteria. Passive immunization in mice using monoclonal antibodies to Pf, resulted in significant efficacy in the treatment of infection. These results show a the direct, pathogenic role of phage virions in bacterial infections.

Research sources:

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.

Johanna M Sweere, Jonas D Van Belleghem, Heather Ishak, Michelle S Bach, Medeea Popescu, Vivekananda Gupta Sunkari, Gernot Kaber, Robert Manasherob, Gina A Suh, Xiou Cao, Christiaan R de Vries, Dung N Lam, Payton L Marshall, Maria K Birukova, Ethan Katznelson, Daniel Vasco Lazzareschi, Seetharaman Balaji, Sundeep G Keswani, Thomas R Hawn, Patrick R Secor, Paul L Bollyky. Published in Science 2019 | DOI:10.1126/science.aat9691

The behaviour of virulent bacteriophages in comparison to temperate bacteriophages would differ, as their use of the bacterium in question is very different. For virulent bacteriophages, the bacterium is a host for replication and survival. For temperate bacteriophages, they infuse their DNA with the one of the bacterium and therefore the survival of the bacterium would also allow their own survival. This symbiosis enhances the activity of the bacteria to suppress the immune system and reduce sensitivity to antibiotics.

More questions on the topic:

It would be interesting to know whether temperate bacteriophages simply fuse with the bacterium’s genome, or if they have any capabilities on changing the bacterium’s genome?
Under what circumstances would the temperate bacteriophage decide to switch to the lytic cycle?
The above article mentions that the immune system did not recognize the Pseudomonas aeruginosa with a Pf lysogenic filamentous phage as its target. If a temperate bacteriophage has any effect on the bacterium’s genome, how would a virulent bacteriophage view a bacterium that has a temperate bacteriophage infused in its genome? Will a virulent bacteriophage recognize the bacterium as an object to attack or would it now be viewed differently?

In conclusion, it should be noted that from a practical point of view, all manufactured bacteriophages are exclusively virulent phages (using the lytic cycle). These bacteriophages and do not carry the capability of enhancing the host bacteria, which was shown by the temperate bacteriophages, described in the second study above.

Should you have information that may respond to any of the questions mentioned above, feel free to write to us.

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